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Genome-wide RNA structure changes during human neurogenesis modulate gene regulatory networks

ABSTRACT: RNAs structures play central roles in various cellular processes, and can be remodeled upon binding to cellular factors such as RNA binding proteins (RBP). However, how widespread this remodeling is and whether structural changes can serve as additional regulatory steps for other regulators remains under-explored. Here, we assayed RNA structural dynamics, gene expression, translation and decay during different stages of human neuronal differentiation to understand the impact of RNA structures in stem cell regulation. RBP binding resulted in wide-spread RNA structure changes during early neuronal differentiation. Structure changes act as a common mechanism for RBPs to modulate the binding of additional RBPs and miRNAs to coordinate gene expression temporally. In particular, we showed that PUM2 binding on LIN28A resulted in RNA structure changes that enabled miR-30 binding, leading to downregulation of LIN28A. Compensatory mutagenesis experiments that lock specific structural states confirmed the importance of PUM2-induced structure changes in miR-30 regulation. This systematic study broadens our understanding of RNA structural dynamics during human neuronal differentiation and illustrates the wide-spread and complex role of RBPs in regulating RNA structures for gene regulation during human development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236224 | GEO | 2023/07/01

REPOSITORIES: GEO

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Genome-wide structure changes during neuronal differentiation drive gene regulatory networks

Project description:RNAs structures play central roles in various cellular processes, and can be remodeled upon binding to cellular factors such as RNA binding proteins (RBP). However, how widespread this remodeling is and whether structural changes can serve as additional regulatory steps for other regulators remains under-explored. Here, we assayed RNA structural dynamics, gene expression, translation and decay during different stages of human neuronal differentiation to understand the impact of RNA structures in stem cell regulation. RBP binding resulted in wide-spread RNA structure changes during early neuronal differentiation. Structure changes act as a common mechanism for RBPs to modulate the binding of additional RBPs and miRNAs to coordinate gene expression temporally. In particular, we showed that PUM2 binding on LIN28A resulted in RNA structure changes that enabled miR-30 binding, leading to downregulation of LIN28A. Compensatory mutagenesis experiments that lock specific structural states confirmed the importance of PUM2-induced structure changes in miR-30 regulation. This systematic study broadens our understanding of RNA structural dynamics during human neuronal differentiation and illustrates the wide-spread and complex role of RBPs in regulating RNA structures for gene regulation during human development.

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Global analysis of the RNA-protein interaction and RNA secondary structure landscapes of the Arabidopsis nucleus

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Project description:Protein binding is essential to the transport, decay and regulation of almost all RNA molecules. However, the structural preference of protein binding on RNAs and their cellelar functions and dynamics upon changing environmental condictions are poorly understood. Here, we integrated various high-throughput data and introduced a computational framework to describe the global interactions between RNA binding proteins (RBPs) and structured RNAs in yeast at single-nucleotide resolution. We found that on average, in terms of percent total lengths, ~15% of mRNA untranslated regions (UTRs), ~37% of canonical ncRNAs and ~11% of long ncRNA (lncRNAs) are bound by proteins. The RBP binding sites, in general, tend to occur at single-stranded loops, with evolutionarily conserved signatures, and often facilitate a specific RNA structure conformation in vivo. We found that four nucleotide modifications of tRNA are significantly associated with RBP binding. We also identified various structural motifs bound by RBPs in the UTRs of mRNAs, associated with localization, degradation and stress responces. Moreover, we identified >200 novel lncRNAs bound by RBPs, and about half of them contain conserved secondary structures. We present the first ensemble pattern of RBP binding sites in the structured noncoding regions of a eukaryotic genome, emphasizing their structural context and cellular functions. Duplicate gPAR-CLIP libraries were sequenced from yeast strains for each of three conditions: log-phase growth, growth after 2 hour glucose starvation, and growth after 2 hour nitrogen starvation. polyA RNAs were isolated for all conditions. Total RNA were isolated from log phase growth conditions. Sucrose gradient fractionation was performed: some RNAs were isolated from the "light" fraction (lighter than 40S ribosome) and some from the "heavy" fraction. gPAR-CLIP libraries were used to determine regions of RNA bound by proteins.

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Embryonic lumenogenesis is controlled by selective mRNA decay triggered by LIN28A relocation [miCLIP]

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